Role of the p53 homolog p73 in cancer

描述：(申请人提供)p73股份实质结构和 与P53的功能同源性。P73可以整合不同的死亡信号 体内包括DNA损伤、癌基因失控和T细胞活化 受体，作为响应，介导原代细胞和肿瘤细胞的凋亡。为 例如，我们最近发现内源性p73是由 癌基因E2F1、cMyc和Eta。尽管如此，p73‘S在肿瘤发生中的确切作用 这是因为目前的基因和表达数据不支持经典的 克努森式的抑制者角色。小鼠p73基因受两个启动子调控 P1和P2，其中P1产生全长P73，P2产生显性负片 缺少反式激活结构域的deltaNp73。在小鼠中，deltaNp73扮演着一个 抗细胞凋亡在对抗P53介导的神经元死亡中的重要作用 在塑造发育中的大脑的过程中。我们有证据表明人类p73 也有一个功能性的P2启动子，它在 肿瘤。在这里，我们假设人类p73具有抗肿瘤保护作用 活体，尽管比p53弱，后者是表观遗传的，而不是遗传的 靶向肿瘤。我们进一步假设，表观遗传的一个主要机制 P73靶向是通过p73之间的显性负相互作用介导的。 和i)具有p53突变的肿瘤中的突变型p53蛋白(“双重打击”)和ii) P73本身的反式激活缺陷亚型，如deltaNp73。这 表观遗传学模型可以解释：1)人类癌症中缺乏p73突变， Ii)p73基因经常与肿瘤相关的过度表达，因为 显性负异构体的贡献目前尚不清楚，iii) P73基因缺陷小鼠未能发展为自发性肿瘤，因为 P53的存在可以替代p73的抑制功能。我们会 在人类身上使用遗传、功能和生化方法来测试这一概念 肿瘤、细胞系和产生可诱导的deltaNp73转基因小鼠 模特。我们还将探索其他已建立的人类致癌基因是否可以 激活P73。

DESCRIPTION: (provided by applicant) p73 shares substantial structural and functional homology with p53. p73 can integrate diverse incoming death signals in vivo including DNA damage, oncogene deregulation and activation of T cell receptors, and in response mediate apoptosis in primary and tumor cells. For example, we recently showed that endogenous p73 is induced and activated by the oncogenes E2F1, cMyc and EtA. Nevertheless, p73's precise role in tumorigenesis is unclear because current genetic and expression data do not support a classic Knudson-type suppressor role. The mouse p73 gene is regulated by two promoters P1 and P2, with P1 producing full length p73 and P2 producing dominant negative deltaNp73 that lacks the transactivation domain. In mouse, deltaNp73 plays an important anti-apoptotic role in counteracting p53-mediated neuronal death during the sculpting of the developing brain. We have evidence that human p73 also has a functional P2 promoter which is generating deltaNp73 transcripts in tumors. Here we hypothesize that human p73 has an anti-tumor safeguard role in vivo, albeit weaker than p53, which is epigenetically rather than genetically targeted in tumors. We further hypothesize that a main mechanism of epigenetic p73 targeting is mediated through dominant negative interactions between p73 and i) mutant p53 proteins in tumors with p53 mutations ('double hit') and ii) transactivation-deficient isoforms of p73 itself such as deltaNp73. This epigenetic model could explain i) the lack of p73 mutations in human cancer, ii) the frequent tumor-associated overexpression of the p73 gene, since the contribution by dominant negative isoforms is currently not known and iii) the failure of p73-deficient mice to develop spontaneous tumors, because the presence of p53 could substitute for the suppressor function of p73. We will test this notion using genetic, functional and biochemical approaches in human tumors, cells lines and by generating an inducible deltaNp73 transgenic mouse model. We will also explore whether other established human oncogenes can activate p73.